Aldose reductase (AR) of the polyol pathway has been implicated in some of the disabling complications of diabetes. We have now successfully completed the protein sequence for aldose reductase using cDNA sequencing and primer extension analysis of AR mRNA. The primary structure of AR consists of an open reading frame of 948 nucleotides encoding for a 316 amino acid polypeptide (including the initiation methionine) with a molecular weight of 35,797. Secondary structure predictions indicate that AR is over 50% beta-Sheet. Protein comparisons have previously revealed structural relatedness (41% to 57%) among vertebrate aldose reductase, aldehyde reductase, prostaglandin F synthase and the frog lens protein rho-crystallin. This superfamily can now be extended to prokaryotes by the inclusion of Corynebacterium 2,5 diketo-D-gluconate reductase. This more distantly related protein shares 30-40% identity with the vertebrate enzymes. Southern blot analysis indicated the existence of a multi-gene family for AR. Since our amino acid sequence data for AR have revealed considerable sequence similarity to other aldo/keto reductases, it will be interesting to elucidate the relationship between genes encoding these proteins and a gene family for AR.